The Adjunctive Decision

Experts share their experiences on adding adjunctive therapy in patients with glaucoma.

BY DIANE DONOFRIO ANGELUCCI

Most ophthalmologists agree that it's best to treat patients with glaucoma using as few medications as possible. But when IOP fails to respond adequately to monotherapy, it may be time to add an adjunctive drug — or is it?

Adding an adjunctive drug is a complex undertaking not suited to a cookbook approach. This article shares experts' tips for individualizing adjunctive treatment to each patient.

Determine if an Adjunct is Necessary

"One of the things most ophthalmologists forget is, rather than jumping to add another agent, they should make sure the first agent was really effective," says Alan L. Robin, M.D., professor of ophthalmology, University of Maryland, College Park, and associate professor, Department of Ophthalmology, Johns Hopkins University, Baltimore. If a one-eye therapeutic trial indicates the drug is not effective enough, consider switching to a drug in another class, he suggests. "Often we just knee-jerk and add another medicine rather than thinking about changing classes of medicines," Dr. Robin says.

George Spaeth, M.D., Esposito Research Professor, Wills Eye Institute, Philadelphia, recommends monitoring a patient over time to determine whether disability and damage are occurring at a specific IOP, the rate of change and whether that patient is at risk. "If a person is already taking a medication, but on that medication his optic nerve continues to get worse or his visual field continues to get worse, clearly his pressure needs to be lower than that," he says.

Keep in mind that your target pressure was an educated guesstimate, says Tony Realini, M.D., associate professor of ophthalmology, West Virginia University, Morgantown. "It may have been made several years ago when you first met the patient and now you have several years of additional data," he says. "Is there anything in that data that might suggest to you that your target pressure estimate needs to be adjusted upward or downward?" Patients may not need adjunctive therapy if their risk of progression appears to be less than you originally believed, he says.

If tests suggest disease progression, confirm your findings. "I don't generally advance treatment when a patient who has had a stable visual field for some time suddenly has an apparent progression by his new visual field," Dr. Realini says. "I'll repeat the test and confirm that change before I advance therapy because often times — in fact, perhaps the majority of times — an apparent change in the visual field is just an aberration."

Weigh the Options

If you began treating your patient with a prostaglandin analog (bimatoprost 0.03% [Lumigan, Allergan], travoprost 0.004% [Travatan Z, Alcon] and latanoprost 0.005% [Xalatan, Pfizer]), adjunctive choices typically include beta-blockers, carbonic anhydrase inhibitors (CAIs), alpha-agonists and combination drugs.

Although beta-blockers achieve similar results to prostaglandin analogs in decreasing pressure during the day, in combination with prostaglandin analogs they've been disappointing because on average they achieve a couple of millimeters of IOP reduction, says Robert J. Noecker, M.D., M.B.A., director of the glaucoma service and vice chairman at the University of Pittsburgh Medical Center Eye Center.

Thomas K. Mundorf, M.D., in private practice in Charlotte, N.C., finds that beta-blockers can still be helpful with prostaglandins. "While research would suggest drugs like brimonidine-purite (Alphagan P, Allergan), brinzolamide hydrochloride (Azopt, Alcon) and dorzolamide hydrochloride ophthalmic solution (Trusopt, Merck) may add to prostaglandins better than beta-blockers, we still find that beta-blockers like timolol ophthalmic solution (Betimol, Vistakon) help lower IOP in patients on prostaglandins," he says. "If a physician has tried two prostaglandins and gets a modest reduction in IOP, I believe beta-blockers can help more than in a situation where the prostaglandin has profoundly dropped the IOP."

In practice, Dr. Robin tends to begin timolol maleate (on the $4 list at Wal-Mart and Target) as an adjunct to a prostaglandin analog because generic forms are inexpensive. "If cost is not an issue and adjunctive therapy is, I usually use a topical CAI. The advantage is that they're safe drugs," Dr. Robin says, adding that CAIs have minimal systemic side effects and hardly any ophthalmic side effects.

"The advantages of beta-blockers are they are cheap, they are often able to be dosed once a day and we are very familiar with them because we've had them the longest of virtually all of our other drugs," Dr. Realini says.

However, Dr. Realini is deterred by systemic side effects associated with beta-blockers and their minimal efficacy with prostaglandin analogs. "In numerous phase 4 clinical trials, CAIs seem to provide reasonable additive IOP reduction to prostaglandin monotherapy," Dr. Realini says. "They are very well tolerated. They have very few if any systemic contraindications, short of sulfonamide allergy." Although they are indicated for three times daily dosing, he says, compelling evidence indicates twice-daily dosing in combination with a prostaglandin can achieve maximum IOP reduction.

Dr. Noecker says CAIs have a good safety profile, but probably a little higher tolerability side-effect profile than the alpha-agonists, often giving a patient a bad taste in the mouth and being less benign to the cornea. He explains that some studies have shown CAIs to have similar efficacy to beta-blockers and alpha-agonists when used as adjuncts, but others have shown they do not work as well.

Alpha-agonists in the form of brimonidine-purite have good safety and efficacy profiles, Dr. Noecker says. "And these drugs have a history of working quite well in combination with the prostaglandin analogs." However, he says, they do not have as long a half-life as beta-blockers, so IOP fluctuates a little more between doses.

Alpha-agonists often require three doses a day. "Brimonidine also has one of the highest discontinuation rates of all of our drugs largely because there's a late-appearing chronic blepharoconjunctivitis that appears in a substantial number of patients on brimonidine," Dr. Realini says. Systemic side effects can include sleepiness and a decrease in blood pressure.

Although Dr. Spaeth uses a variety of drugs, he uses a great deal of dorzolamide hydrochloride/timolol maleate (Cosopt, Merck), which is a combination of a topical CAI and beta blocker. "It's more potent than either one alone and it works very well," he says. "As a matter of fact, it's a very nice drug to start patients on when you need more pressure lowering than you think you're going to get from either one."

"Cosopt and Combigan [brimonidine tartrate/timolol maleate, Allergan] have reasonably good efficacy because they contain two active ingredients in one drop," Dr. Noecker says. "The question always when using combination drugs before adding on individual components is you're never sure which component may be doing more of the work in terms of lowering IOP."

He explains that Combigan appears to have a slightly better efficacy than Cosopt and probably a little better tolerability profile. And it combines a beta-blocker and brimonidine, so the components are well known and have a long history, Dr. Noecker says. Dr. Mundorf adds that Cosopt and Combigan can lower IOP to a similar degree as prostaglandins and can be considered in situations where the patient is a poor responder to prostaglandins or has some intolerance to prostaglandins.

Dr. Realini says that adding Cosopt to prostaglandin monotherapy is not consistent with the product's label but is reasonable if patients need an additional large pressure reduction. "Interestingly, now that Combigan is approved, adding it to someone inadequately controlled on prostaglandin monotherapy or switching to Combigan from prostaglandin mono therapy is consistent with the product's label and is an option." However, Dr. Realini says that prefers not to add two drugs at once because he cannot determine whether the patient would have responded to one drop instead of two, and combination drugs subject patients to two sets of potential side effects.

Temper Expectations

Rather than relying on expectations about specific drugs, ophthalmologists should base their decisions on empirical trials, Dr. Spaeth says. For example, topical CAI reduced IOP from 45 to 15 mm Hg in a patient after beta-blockers and prostaglandin failed to do the trick. "Topical CAIs aren't supposed to lower pressure 30 mm Hg, but they do in certain people," he says.

"It's important to recognize that most drugs are evaluated as monotherapy agents in the phase 3 regulatory studies and the IOP reduction that a drug delivers in monotherapy usage is not something that you should expect to see in adjunctive usage," Dr. Realini says. "So if you're used to a beta-blocker dropping pressure 5 to 7 points, don't expect 5 to 7 incremental points when adding it to a prostaglandin. It doesn't work as well in adjunctive therapy as it does in monotherapy. And that's true of all of the drugs."

Tailor Therapy to the Patient

"There is no drug of choice for anybody that fits everybody," Dr. Spaeth says. "Everybody has their own drug of choice." For example, he recently started a young woman on a beta-blocker because he didn't think she would want a drug that would affect her appearance. "So what you do is, on the basis of the patient's needs, characteristics, all the things that fit into it, you pick a drug appropriate for that particular person," he says.

Review the patient's medical history carefully when choosing a drug. "If you're going to use an adjunctive therapy like a beta-blocker, you want to make sure the patient has no history of impotence if it's a man, no history of asthma, no history of congestive heart failure that is not stable and there's no history of unstable depression, which can be exacerbated by a beta-blocker," Dr. Robin says.

Disease stage is also important. "The worse the patient's disease is, the more likely we are to go with the more efficacious combination drugs at least to figure out and determine if medical therapy is going to work at all," Dr. Noecker says. "The less severe a patient's disease is, then we can move more slowly and add on individual components sequentially and try to minimize therapy that way."

You also need to consider whether your patient will be able to adjust to a multi-drug regimen requiring dosing multiple times a day.

Monitor Patient Response

Once a patient begins any therapy, it is important to monitor response. "I almost always use one-eye therapeutic trials," Dr. Spaeth says. By treating the patient in one eye initially, you can determine whether the drug is working.

Dr. Noecker also uses a one-eye trial. He sees patients at different times of day to determine how much variation is occurring throughout the day. Patients return 3 to 4 weeks after beginning a new treatment, when Dr. Noecker hopes to see at least a 15% reduction over the IOP with the initial drug. Once patients reach their target pressures, he sees them 3 to 6 months later. He then performs visual field testing, imaging and clinical exams with an IOP check at 6-month intervals.

"Because pressure does fluctuate a lot, I don't usually make the determination of adjunctive efficacy at the first visit after adding the adjunctive drug," Dr. Realini says. He obtains a couple of measurements over time before deciding whether monotherapy or the adjunctive therapy works.

During patient visits, be sure to stress compliance. During Dr. Robin's study using electronic monitoring to determine adherence in patients using once-daily prostaglandin analogs compared with once-daily prostaglandin analogs and an adjunctive drug, adherence to the second drug was poorer, with 37% of patients making more than five dosing errors.¹ "The more complex a medical regimen is, the less likely somebody is going to comply with it accurately," Dr. Robin says.

Patients also may mix up their drops. "There are lots of medications where the tops are interchangeable," Dr. Robin says. If you talk to patients about the "orange-topped drop" or the "teal-topped drop," they may be using the drugs inappropriately if they have switched the tops.

"If you don't get a big drop in pressure after adding adjunctive therapy, it's important to ask how far apart they are spacing the drops," Dr. Realini says. Patients can mistakenly instill two different drops one right after the other, not realizing the second washed away the first.

Be Alert to Difficulties

Economic circumstances increasingly influence drug choices. If the drug is not listed on a patient's formulary, you must decide whether the increased cost is worthwhile to the patient or you need to choose an alternative drug, Dr. Noecker says.

Drug combinations also can cause problems. Dr. Spaeth has discontinued a medication in patients using multi-drug therapy because of severe blepharitis and found that the patients' IOP dropped. "So not only can multiple medications make the eyes irritated, but they can actually make the pressure go up," he says.

Older patients with glaucoma may not realize new symptoms are side effects of their eye drops, Dr. Realini says. When prescribing a drug, he explains potential side effects and encourages patients to report them if they occur. OM

Editor's Note: Dr. Robin is a consultant for ISTA, Merck and Alcon and is on the speakers' bureau for Pfizer, Alcon, Merck and ISTA. Dr. Spaeth receives grants from Alcon, Pfizer, Merck and Allergan. Dr. Realini is on the speakers' bureau for Merck, Pfizer and Alcon. Dr. Noecker is a consultant for Allergan and is on the speakers' bureau for Alcon, Merck, ISTA and Allergan. Dr. Mundorf has received research grants from Aerie, Alcon, Allergan, ISTA, Inspire and Novartis.

Reference

1. Robin AL, Novack GD, Covert DW, et al. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol. 2007;144:533-540.